Monogenic Immune Disorders Reshape Evaluation of Rheumatic Disease

MONOGENIC immune disorders present across adulthood with atypical manifestations that challenge classic Mendelian paradigms and clinical guidelines. Genomic sequencing advances show that single gene alterations, arising via germline transmission or postzygotic somatic mosaicism, represent critical etiologies of systemic inflammation and immune breakdown in adult populations. Many individuals display incomplete penetrance or variable expressivity, often fulfilling classification criteria for systemic lupus erythematosus, polyarteritis nodosa, or relapsing polychondritis. Consequently, recognizing these genetic mimics is paramount to selecting effective targeted therapies.

Clinical Spectrum of Monogenic Immune Disorders

Germline inborn errors of immunity encompass autoinflammatory phenotypes, broad autoimmune syndromes, and organ-specific pathology. Autoinflammatory diseases stem primarily from innate immune dysregulation, categorized into inflammasome-driven disorders, type I interferonopathies, and NF-κB-mediated pathways. Gain-of-function variants in STAT4 drive childhood or adult-onset pansclerotic morphea responsive to ruxolitinib. Similarly, novel variants in NLRP3 can present solely with progressive sensorineural hearing loss without systemic fevers, resolving with interleukin-1 receptor antagonism.

Monogenic lupus variants disrupt efferocytosis, interferon regulation, or lymphocyte tolerance. Gain-of-function TLR7 variants enhance guanosine affinity and downstream NF-κB signaling, promoting aberrant B-cell survival independent of germinal centers. In diseases of adaptive dysregulation, gain-of-function mutations in JAK1 generate refractory atopy, eosinophilia, dermatitis, and colitis, establishing the syndromic spectrum known as JAACD. Mutations in IKZF1 perturb lymphocyte differentiation, predisposing patients to autoimmune disease, IgG4-related pathology, and lymphoid malignancy.

Somatic Variants and Practical Genetic Testing

Somatic mutations acquired during life represent an expanding class of adult-onset conditions. Somatic UBA1 mutations cause VEXAS syndrome, characterized by severe systemic inflammation, chondritis, cytopenias, and myelodysplastic syndrome in mature adults. Postzygotic mosaicism in MEFV, NLRP3, NLRC4, and NOD2 also produces clinical phenocopies of classic autoinflammatory illnesses later in life.

Clinicians should consider genetic testing in patients with atypical features, coexisting autoinflammation and immunodeficiency, significant family history, or disease refractory to conventional immunosuppression. Targeted panels, whole-exome sequencing, and whole-genome sequencing provide powerful diagnostic avenues. Identifying a definitive molecular defect optimizes patient outcomes, supports genetic counseling, and allows targeted, mechanism-based pharmacological interventions.

Reference

Liebowitz J et al. Monogenic Autoimmune and Autoinflammatory Disorders in Adulthood: Recent Discoveries and Implications for Rheumatology Practice. Rheumatology (Oxford). 2026;65(6):keag299.